Indole-2,3-dione-3-oxime derivatives, their preparation and use

ABSTRACT

The present patent application discloses compounds having the formula ##STR1## or a pharmaceutically acceptable salt thereof wherein R 1 , X and R 5  have the meanings set further in the specification. 
     A is a ring of five to seven atoms fused with the benzo ring at the positions marked a and b. 
     The compounds are useful in the treatment of cerebrovascular disorders for example.

This application is a 371 of PCT/EP95/03593, filed Sep. 12, 1995.

The present invention relates to novel ring fused compounds capable ofantagonizing the effect of excitatory amino acids, such as glutamate, amethod of treatment therewith, pharmaceutical compositions comprisingthe compounds and to a method of preparing the novel compounds of theinvention.

OBJECT OF THE INVENTION

It is an object of the present invention to provide novel glutamateantagonists which are useful in the treatment of disorders or diseasesin mammals, including a human, and especially in the treatment ofdisorders or diseases which are responsive to glutamate and/or aspartatereceptor antagonists of such mammals.

Another object of the present invention is to provide a method oftreating disorders or diseases of mammals, including a human, responsiveto glutamate and/or aspartate receptor antagonists which comprisesadministering to a mammal in need thereof a compound of the invention.

A third object of the present invention is to provide novelpharmaceutical compositions for the treatment of disorders or diseasesof mammals, including a human, responsive to glutamic and/or asparticacid receptor antagonists.

Other objectives of the present invention will be apparent to theskilled person hereinafter.

BACKGROUND OF THE INVENTION

Excessive excitation by neurotransmitters can cause the degeneration anddeath of neurons. It is believed that this degeneration is in partmediated by the excitotoxic actions of the excitatory amino acids (EAA),glutamate and aspartate, at the N-methyl-D-aspartate (NMDA), thealfa-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)receptor, and the kainate receptor. This excitotoxic action isresponsible for the loss of neurons in cerebrovascular disorders such ascerebral ischemia or cerebral infarction resulting from a range ofconditions, such as thromboembolic or haemorrhagic stroke, cerebralvasospasm, hypoglycaemia, cardiac arrest, status epilepticus, perinatalasphyxia, anoxia such as from near-drowning, pulmonary surgery andcerebral trauma as well as lathyrism, Alzheimer's, and Huntington'sdiseases.

The compounds of the present invention may also be useful in thetreatment of Amyotrophic Lateral Sclerosis (ALS), schizophrenia,Parkinsonism, epilepsy, anxiety, pain and drug addiction.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows the 2-vessel occlusion in gerbils.

SUMMARY OF THE INVENTION

The invention then, inter alia, comprises the following, alone or incombination:

A compound having the formula ##STR2## or a pharmaceutically acceptablesalt thereof wherein

R¹ is hydrogen, alkyl or benzyl;

X is NOR², wherein R² is acyl;

R⁵ is

phenyl,

naphthyl,

thienyl,

pyridyl,

all of which may be substituted one or more times with substituentsselected from the group consisting of halogen, CF₃, NO₂, amino, alkyl,alkoxy, phenyl and SO₂ NR'R" wherein R' and R" each independently arehydrogen or alkyl or wherein R' and R" together is (CH₂)_(m) wherein mis 2, 3, 4, 5 or 6;

A is a ring of five to seven atoms fused with the benzo ring at thepositions marked a and b, and formed by the following bivalent radicals:

a-NR¹² --CH₂ --CH₂ -b

a-CH₂ --CH₂ --NR¹² -b

a-CH₂ --NR¹² --CH₂ -b,

a-CH₂ --CH₂ --NR¹² --CH₂ -b,

a-CH₂ --NR ¹² --CH₂ --CH₂ -b,

a-CH₂ --CH₂ --CH₂ --NR¹² -b,

a-NR¹² --CH₂ --CH₂ --CH₂ -b,

a-CH₂ --CH₂ --NR¹² --CH₂ --CH₂ -b,

a-CH₂ --CH₂ --CH₂ --NR¹² --CH₂ -b,

a-CH₂ --NR¹² --CH₂ --CH₂ --CH₂ -b,

a-CH₂ --CH₂ --CH₂ --CH₂ --NR² -b,

a-NR¹² --CH₂ --CH₂ --CH₂ --CH₂ -b,

wherein

R¹² is hydrogen, CH₂ CH₂ OH, or alkyl;

a compound as above having the formula ##STR3## or a pharmaceuticallyacceptable salt thereof; wherein X, R¹, R⁵, and R¹² have the meaningsset forth above;

a compound as above having the formula ##STR4## or a pharmaceuticallyacceptable salt thereof; wherein X, R¹, R⁵, and R¹² have the meaningsset forth above;

a compound as above having the formula ##STR5## or a pharmaceuticallyacceptable salt thereof; wherein X, R¹, R⁵, and R¹² have the meaningsset forth above;

a compound as above having the formula ##STR6## or a pharmaceuticallyacceptable salt thereof; wherein X, R¹, R⁵, and R¹² have the meaningsset forth above;

a compound as above, which is

8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo3,2-h!isoquinoline-2,3-dione-3-O-acetyloxime,

8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo3,2-h!isoquinoline-2,3-dione-3-O-(N-ethylcarbamoyl)oxime,

8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo3,2-h!isoquinoline-2,3-dione-3-O-pivaloyloxime,

7-ethyl-5-phenyl-1,6,7,8-tetrahydrobenzo2,1-b:3,4-c!-dipyrrole2,3-dione-3-O-acetyloxime,

8-methyl-5-(4-(N,N-dimethylsulphamoyl)phenyl)-6,7,8,9-tetrahydro-1H-pyrrolo3,2-h!isoquinoline-2,3-dione-3-O-(N-ethylcarbamoyl)oxime,

8-methyl-5-(4-(N,N-dimethylsulphamoyl)phenyl)-6,7,8,9-tetrahydro-1H-pyrrolo3,2-h!isoquinoline-2,3-dione-3-O-(N-cyclohexylcarbamoyl)oxime, or

8-methyl-5-(4-(N,N-dimethylsulphamoyl)phenyl-6,7,8,9-tetrahydro-1H-pyrrolo3,2-h!isoquinoline-2,3-dione-3-O-(N-t-butylcarbamoyl)oxime,

or a pharmaceutically acceptable salt thereof;

a pharmaceutical composition comprising a therapeutically-effectiveamount of a compound as any above together with at least onepharmaceutically-acceptable carrier or diluent;

a method of treating a disorder or disease of a mammal, including ahuman, which disorder or disease is responsive to glutamic and/oraspartic acid receptor antagonists, which comprises administering to apatient in need thereof an effective amount of a compound as any above;

a method as above wherein lathyrism, Alzheimer's disease, Huntington'sdiseases, ALS, schizophrenia, Parkinsonism, epilepsy, anxiety, pain,drug addiction, or cerebrovascular disorders are treated;

the use of a compound as any above for the manufacture of a medicamentfor the treatment of a disorder or disease of a mammal, including ahuman, which disorder or disease is responsive to glutamic and/oraspartic acid receptor antagonists;

the use as above for the manufacture of a medicament for the treatmentof a disorder or disease of a mammal, including a human, which disorderor disease is lathyrism, Alzheimer's disease, Huntington's diseases,ALS, schizophrenia, Parkinsonism, epilepsy, anxiety, pain, drugaddiction, or cerebrovascular disorders; and

a method of preparing a compound as any above comprising the step ofreacting a compound having the formula ##STR7## wherein A, a, b, R¹, andR⁵ have the meanings set forth above, with

a) an activated acyl derivative, preferably in the form of an carboxylicacid halide or anhydride, or

b) an isocyanate

to form a compound of the invention.

Examples of pharmaceutically acceptable addition salts include inorganicand organic acid addition salts such as the hydrochloride, hydrobromide,phosphate, nitrate, perchlorate, sulphate, citrate, lactate, tartrate,maleate, fumarate, mandelate, benzoate, ascorbate, cinnamate,benzenesulfonate, methanesulfonate, stearate, succinate, glutamate,glycollate, toluene-p-sulphonate, formate, malonate,naphthalene-2-sulphonate, salicylate and the acetate. Such salts areformed by procedures well known in the art.

Other acids such as oxalic acid, while not in themselvespharmaceutically acceptable, may be useful in the preparation of saltsuseful as intermediates in obtaining compounds of the invention andtheir pharmaceutically acceptable acid addition salts.

Halogen is fluorine, chlorine, bromine, or iodine.

Alkyl means a straight chain or branched chain of from one to six carbonatoms or cyclic alkyl of from three to seven carbon atoms, including butnot limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl; methyl, ethyl, propyl and isopropyl are preferred groups.

Alkoxy is O-alkyl, wherein alkyl is as defined above.

Amino is NH₂ or NH-alkyl or N-(alkyl)₂, wherein alkyl is as definedabove.

Acyl is (C═O)--R° or (C═S)--R° wherein R° is alkyl; phenyl which may besubstituted one or more times with substituents selected from the groupconsisting of halogen, CF₃, NO₂, amino, alkyl, alkoxy, phenyl and SO₂NR'R" wherein R' and R" each independently are hydrogen or alkyl orwherein R' and R" together is (CH₂)_(m) wherein m is 2, 3, 4, 5 or 6; orR° is benzyl; or NR^(III) R^(IV) wherein R^(III) and R^(IV) eachindependently are hydrogen or alkyl or wherein R^(III) and R^(IV)together is (CH₂)_(p) wherein p is 2, 3, 4, 5 or 6.

The compounds of this invention may exist in unsolvated as well as insolvated forms with pharmaceutically acceptable solvents such as water,ethanol and the like. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of this invention.

Some of the compounds of the present invention exist in (+) and (-)forms as well as in racemic forms. Racemic forms can be resolved intothe optical antipodes by known methods, for example, by separation ofdiastereomeric salts thereof, with an optically active acid, andliberating the optically active amine compound by treatment with a base.Another method for resolving racemates into the optical antipodes isbased upon chromatography on an optical active matrix. Racemic compoundsof the present invention can thus be resolved into their opticalantipodes, e.g., by fractional crystallization of d- or I- (tartrates,mandelates, or camphorsulphonate) salts for example. The compounds ofthe present invention may also be resolved by the formation ofdiastereomeric amides by reaction of the compounds of the presentinvention with an optically active activated carboxylic acid such asthat derived from (+) or (-) phenylalanine, (+) or (-) phenylglycine,(+) or (-) camphanic acid or by the formation of diastereomericcarbamates by reaction of the compounds of the present invention with anoptically active chloroformate or the like.

Additional methods for the resolvation of optical isomers, known tothose skilled in the art may be used, and will be apparent to theaverage skilled in the art. Such methods include those discussed by J.Jaques, A. Collet, and S. Wilen in "Enantiomers, Racemates, andResolutions", John Wiley and Sons, New York (1981).

Furthermore, as the compounds of the invention are oximes they can existin two forms, syn- and anti-form, depending on the arrangement of thesubstituents around the --C═N-- double bond. The present inventionincludes both the syn- and anti-form of the compounds of the inventionas well as mixtures thereof. Acids catalyzes anti-syn isomerization.

Starting materials for the processes described in the presentapplication are known or can be prepared by conventional methods fromcommercially available chemicals.

The products of the reactions described herein are isolated byconventional means such as extraction, crystallization, distillation,chromatography, and the like.

BIOLOGICAL ACTIVITY

The compounds of the invention exhibit valuable biological propertiesbecause of their strong excitatory amino acid (EAA) antagonizingproperties at the AMPA((RS)-alfa-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) bindingsite.

In Vitro activity (receptor affinity):

The compounds of the present invention has been tested for theiraffinity for the AMPA receptor as described by T. Honore et al.,Neuroscience Letters 54, 27-32 (1985). IC₅₀ values appear from thefollowing Table 1.

                  TABLE 1    ______________________________________    Compound                   IC.sub.50 (μM)    ______________________________________    8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo 3,2-h!-                               0.15    isoquinoline-2,3-dione-3-O-acetyloxime    8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo 3,2-h!-                               0.35    isoquinoline-2,3-dione-3-O-(N-ethylcarbamoyl)oxime    8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo 3,2-h!                               0.19    isoquinoline-2,3-dione-3-O-pivaloyloxime    7-ethyl-5-phenyl-1,6,7,8-tetrahydrobenzo 2,1-b:3,4-c!-                               1.7    dipyrrole-2,3-dione-3-O-acetyloxime    8-methyl-5-(4-(N,N-dimethylsulphamoyl)phenyl)-                               0.038    6,7,8,9-tetrahydro-1H-pyrrolo 3,2-h!isoquinoline-2,3-    dione-3-O-(N-ethylcarbamoyl)oxime    8-methyl-5-(4-(N,N-dimethylsulphamoyl)phenyl)-                               0.014    6,7,8,9-tetrahydro-1H-pyrrolo 3,2-h!isoquinoline-2,3-    dione-3-O-(N-cyclohexylcarbamoyl)oxime    ______________________________________

Also, very importantly the compounds of the present are biologicalprodrugs of the corresponding oxime compounds which all possessextremely high affinity for the AMPA receptors. See WO-A1-94/26747.

The compounds of the invention have also been tested for their abilityto inhibit GABA release from cultured mouse cerebral cortex neuronsusing the following test:

³ H-GABA Release, Cortical Neurons

Background: Neurons which express receptors for excitatory amino acidscan be depolarized by such compounds and this depolarization willultimately lead to a release of transmitter substance from the neurons.Cultured neurons obtained from 15-day-old mouse embryo cortex are mainlyGABAergic and express all types of excitatory amino acid receptors. Thismeans that they can be stimulated by high potassium or by the excitatoryamino acids, NMDA, AMPA and kainate to release their neurotransmitterGABA.

³ H-GABA may be used to label the GABA transmitter pool in the neuronsand the release of ³ H-GABA from the neurons may be used as a simplefunctional model for studies of the effects of excitatory amino acidsand their antagonists.

Method: Cerebral cortices of 16-day-old mouse embryos are chopped in0.4×0.4 mm cubes. The tissue is dissociated by mild trypsinization (0.1%(wt/vol) trypsin, 37° C., 15 min) and subsequently inoculated intopoly-L-lysine-coated 3-cm Petri dishes containing a slightly modifiedDMEM (24.5 mM KCI, 30 mM glucose) supplemented with p-aminobenzoate (7μM), insulin (100 mU/L) and 10% (vol/vol) horse serum. Cells aremaintained in culture for 5-7 days with the addition of the antimitoticagent cytosine arbinoside (40 μM) from day 2 in vitro to prevent glialprofileration. For further details and references, see Drejer et al.Exp. Brain Res. 47, 259 (1982).

Release experiments are performed using the model described by Drejer etal. Life Sci. 38, 2077 (1986). Cerebral cortex neurons cultured in Petridishes (30 mm) are added 100 μM γ-vinyl-GABA one hour before theexperiment in order to inhibit degradation of GABA in the neurons. 30min before the experiment 5 μCi ³ H-GABA is added to each culture andafter this preloading period the cell monolayer at the bottom of thedish is covered with a piece of nylon mesh to protect the cells againstmechanical damage and to facilitate dispersion of medium over the celllayer. The preloading medium is removed and the Petri dishes are placedin a superfusion system consisting of a peristaltic pump continouslydelivering thermostated 37° C. superfusion medium HEPES buffered saline(HBS): 10 mM HEPES, 135 mM NaCl, 5 mM KCl, 0.6 mM MgSO₄, 1.0 mM CaCl₂and 6 mM D-glucose; pH 7.4) from a reservoir to the top of the slightlytilted Petri dish. The medium is continously collected from the lowerpart of the dish and delivered to a fraction collector. Initially, thecells are superfused with HBS for 15 min (flow rate 2 ml/min). Then thecells are stimulated for 30 sec every 4 min by changing the superfusionmedium from HBS to a corresponding medium containing antagonists.

Test subtances are dissolved in 50% DMSO, 48% ethanol. The final DMSOand ethanol concentration in the assay must not exceed 0.1%.

The stimulated release of ³ H-GABA (cpm) are corrected for the meanbasal release(cpm) before and after stimulation.

The stimulated release in the presence of antagonists are expressedrelative to the stimulated release and the IC₅₀ value for the antagonistis calculated (the concentration (μM) of the test substance whichinhibit 50% of the stimulated ³ H-GABA release).

The results obtained are presented in the following table 2:

                  TABLE 2    ______________________________________    Compound                   IC.sub.50    ______________________________________    8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo 3,2-h!                                2.9 μM    isoquinoline-2,3-dione-3-O-acetyloxime    8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo 3,2-h!                               1.40 μM    isoquinoline-2,3-dione-3-O-(N-ethylcarbamoyl)oxime    8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo 3,2-h!                               >3.00 μM    isoquinoline-2,3-dione-3-O-pivaloyloxime    7-ethyl-5-phenyl-1,6,7,8-tetrahydrobenzo 2,1-b:3,4-c!-                                2.7 μM    dipyrrole-2,3-dione-3-O-acetyloxime    8-methyl-5-(4-(N,N-dimethylsulphamoyl)phenyl)-                               0.19 μM    6,7,8,9-tetrahydro-1H-pyrrolo 3,2-h!isoquinoline-2,3-    dione-3-O-(N-ethylcarbamoyl)oxime    ______________________________________

The compound,8-methyl-5-(4-(N,N-dimethylsulphamoyl)phenyl)-6,7,8,9-tetrahydro-1H-pyrrolo3,2-h!isoquinoline-2,3-dione-3-O-(N-ethylcarbamoyl)oxime has also beentested in the following animal moder of global ischaemia:

Transient Forebrain Ischemia Model (2-VO Gerbils)

Gerbils were anaesthetized with halothane, right and left carotidarteries located and occluded for 4 minutes. Animals were kept warmbefore and after the operation using heating lamps. During the operationthe gerbils were placed on heating plates, body temperature controlledand maintained at 37±0.5° C. Postocclusion, the gerbils were divided intwo groups. One group received 30 mg/kg test compound as a bolusinjection i.v. followed by a one hour infusion of 30 mg/kg test compound(total dose was 60 mg/kg). The control group received 0.9% NaCl in thesame infusion volume as the treated group. Four days later, the animalswere sacrificed, brains removed and cooled to -70° C. Thereafter, thebrains were sectioned in 20 mm thick sections of which 5-7 withhippocampal tissue were selected and stained with hematoxylin eosine(HE).

Based upon the degree of hippocampal damage, each hippocampus wascategorised into one of four groups (Group 1: no damage in theCA1-layer; Group 2: the CA1-layer partly damaged; Group 3: the CA1-layercompletely damaged; and Group 4: damage in more than just theCA1-layer). The total ischemic score was obtained as the sum of theright and left scores, thus resulting in ischaemic scores ranging from 2to 8. Mann-Whitney Rank Sum Test was used for statistical evaluation.The test results are presented in FIG. 1.

The compound,8-methyl-5-(4-(N,N-dimethylsulphamoyl)phenyl)-6,7,8,9-tetrahydro-1H-pyrrolo3,2-h!isoquinoline-2,3-dione-3-O-(N-ethylcarbamoyl)oxime havesignificant neuroprotective effect in the gerbil 2-VO model.

PHARMACEUTICAL COMPOSITIONS

While it is possible that, for use in therapy, a compound of theinvention may be administered as the raw chemical, it is preferable topresent the active ingredient as a pharmaceutical formulation.

The invention thus further provides pharmaceutical formulationscomprising a compound of the invention or a pharmaceutically acceptablesalt or derivative thereof together with one or more pharmaceuticallyacceptable carriers therefor and, optionally, other therapeutic and/orprophylactic ingredients. The carrier(s) must be "acceptable" in thesense of being compatible with the other ingredients of the formulationand not deleterious to the recipient thereof.

Pharmaceutical formulations include those suitable for oral, rectal,nasal, topical (including buccal and sub-lingual), vaginal or parenteral(including intramuscular, sub-cutaneous and intravenous) administrationor in a form suitable for administration by inhalation or insufflation.

The compounds of the invention, together with a conventional adjuvant,carrier, or diluent, may thus be placed into the form of pharmaceuticalcompositions and unit dosages thereof, and in such form may be employedas solids, such as tablets or filled capsules, or liquids such assolutions, suspensions, emulsions, elixirs, or capsules filled with thesame, all for oral use, in the form of suppositories for rectaladministration; or in the form of sterile injectable solutions forparenteral (including subcutaneous) use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed. Formulations containingten (10) milligrams of active ingredient or, more broadly, 0.1 to onehundred (100) milligrams, per tablet, are accordingly suitablerepresentative unit dosage forms.

The compounds of the present invention can be administrated in a widevariety of oral and parenteral dosage forms. It will be obvious to thoseskilled in the art that the following dosage forms may comprise, as theactive component, either a compound of the invention or apharmaceutically acceptable salt of a compound of the invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavouring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term "preparation" is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution.

The compounds according to the present invention may thus be formulatedfor parenteral administration (e.g. by injection, for example bolusinjection or continuous infusion) and may be presented in unit dose formin ampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers with an added preservative. The compositions may take suchforms as suspensions, solutions, or emulsions in oily or aqueousvehicles, and may contain formulatory agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilisation from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavours,stabilizing and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavours, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

For topical administration to the epidermis the compounds according tothe invention may be formulated as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also contain one or more emulsifying agents,stabilising agents, dispersing agents, suspending agents, thickeningagents, or colouring agents.

Formulations suitable for topical administration in the mouth includelozenges comprising the active agent in a flavoured base, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert base such as gelatin and glycerin or sucrose andacacia; and mouthwashes comprising the active ingredient in a suitableliquid carrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Theformulations may be provided in single or multidose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomising spray pump.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurized pack with a suitable propellant such as a chlorofluorocarbon(CFC) for example dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, carbon dioxide, or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by provision of a metered valve.

Alternatively the active ingredients may be provided in the form of adry powder, for example a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

In formulations intended for administration to the respiratory tract,including intranasal formulations, the compound will generally have asmall particle size for example of the order of 5 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization.

When desired, formulations adapted to give sustained release of theactive ingredient may be employed.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration and continuous infusion are preferred compositions.

METHOD OF TREATING

The compounds of this invention are extremely useful in the treatment ofcentral nervous system disorders related to their biological activity.The compounds of this invention may accordingly be administered to asubject, including a human, in need of treatment, alleviation, orelimination of a disorder or disease associated with the biologicalactivity of the compounds. This includes especially excitatory aminoacid dependent, including glutamate and/or aspartate dependentpsychosis, excitatory amino acid dependent, including glutamate and/oraspartate dependent anoxia, excitatory amino acid dependent, includingglutamate and/or aspartate dependent ischemia, excitatory amino aciddependent, including glutamate and/or aspartate dependent Parkinsonism,excitatory amino acid dependent, including glutamate and/or aspartatedependent convulsions and excitatory amino acid dependent, includingglutamate and/or aspartate dependent migraine as well as ALS. Suitabledosage ranges are 0.1 to 1000 milligrams daily, 10-500 milligrams daily,and especially 30-100 milligrams daily, dependent as usual upon theexact mode of administration, form in which administered, the indicationtoward which the administration is directed, the subject involved andthe body weight of the subject involved, and further the preference andexperience of the physician or veterinarian in charge.

The following nonlimiting examples illustrate the present inventionfurther.

EXAMPLE 1 ##STR8##

A solution of 4-acetamido-2-methyl-2H-1,3-dihydro-isoindole (10 g) andbromine (3.0 g) in trifluoroacetic acid (150 ml) was stirred at 50° C.for 40 hours. The solution was evaporated in vacuo. The residue wasdissolved in water (300 ml), and pH was adjusted to neutral with sat.Na₂ CO₃. This treatment afforded a crystalline precipitate of theproduct, which was collected by filtration. Yield 9 g, mp. 145°-148°.

EXAMPLE 2 ##STR9##

A solution of potassium nitrate (1.78 g, 8.56 mmol) was added slowly toa solution of 5-bromoisoquinoline in 12 mL H₂ SO₄. After stirring for 3hours the reaction mixture was poured onto ice and neutralized withconc. ammonium hydroxide. The yellow precipitate was extracted withethyl acetate (3×), and the combined organic layers were washed withsaturated NaCl, dried over MgSO₄, filtered and concentrated. The residuewas chromatographed on silica gel (40% ethyl acetate in hexane aseluent) to give 5-bromo-8-nitroisoquinoline in 96% yield.

EXAMPLE 3 ##STR10##

A mixture of 5-bromo-8-nitroisoquinoline (0.99 g, 3.91 mmol) anddimethylsulfate (0.41 mL) in anhydrous DMF (20 mL) was heated at 80° C.for 24 hours. After removing the DMF in vacuo, the isoquinoiinemethylammonium salt was obtained (used without further purification).

In a similar manner the following compound was prepared:

2-ethyl-5-bromo-8-nitroquinolinium ethylsuiphate by reaction withdiethyl sulphate

EXAMPLE 4 ##STR11##

The isoquinoline salt (3.9 mmol) was dissolved in acetic acid (10 mL)and sodium borohydride (0.15 g, 3.97 mmol) was added. After stirring for24 h, the reaction mixture was diluted with a mixture of ethyl acetateand water and potassium carbonate was added portionwise to neutralizethe acetic acid. The aqueous layer was extracted with ethyl acetate(2×), washed with saturated NaCl, dried over MgSO₄, filtered andevaporated. The residue was chromatographed on silica gel (30% ethylacetate in hexane as eluent) to give the light sensitive N-methyl5-bromo-8-nitro-1,2,3,4-tetrahydroisoquinoline (0.47 g, 45% yield).

N-ethyl-5-bromo-8-nitro-1,2,3,4-tetrahydroisoquinoline was preparedaccording to the same procedure. M.p. 52-53° C.

EXAMPLE 5 ##STR12##

A mixture of 4-acetamido-7-bromo-2-methyl-2H-1,3-dihydro-isoindole (0.2g), phenyl boronic acid (137 mg), tetrakis(triphenylphosphine)palladium0! (26 mg), NaHCO₃, (315 mg) was stirred at reflux temperature in amixture of water (3.75 ml) and dimethoxyethane (7.5 ml) for 90 min.After cooling to room temperature the reaction mixture was partitionedbetween EtOAc (25 ml ) and aq. NaOH (2×5 ml 1N). The organic phase wasthen dried over Na₂ SO₄ and evaporated to give4-acetamido-7-phenyl-2methyl-2H-1,3-dihydro-isoindole, mp 160-62° C.

In a similar manner the following compounds were prepared from theappropriate bromides and boronic acids:

4-acetamido-7-phenyl-2-ethyl-2H-1,3-dihydro-isoindole, mp. 67-68° C.

4-acetamido-7-(1-naphthyl)-2-methyl-2H-1,3-dihydro-isoindole mp. 260-62°C.

4-acetamido-5-nitro -7-phenyl-2-methyl-2H-1,3-dihydro-isoindole mp.270-72° C.

5-acetamido-2-methyl-6-nitro-8-phenyl-1,2,3,4-tetrahydro-isoquinolinemp. 214-217° C.

2-methyl-5-phenyl-8-nitro-1,2,3,4-tetrahydro-isoquinoline mp 75-78° C.from reaction between phenyl boronic acid and5-bromo-2-methyl-8-nitro-1,2,3,4-tetrahydro-isoquinoline.2-methyl-5-(4-chlorophenyl)-8-nitro-1,2,3,4-tetrahydro-isoquinoline mp162-163° C.

2-methyl-5-(4-trifluoromethylphenyl)-8-nitro-1,2,3,4-tetrahydro-isoquinolinemp 133-134° C.

2-methyl-5-(4-fluorophenyl)-8-nitro-1,2,3,4-tetrahydro-isoquinoline mp159-160° C.

5-acetamido-2-methyl-8-phenyl-1,2,3,4-tetrahydro-isoquinoline, m.p.140-143° C.

EXAMPLE 6 ##STR13##

A mixture of 4-acetamido-7-bromo-2-methyl-2H-1,3-dihydro-isoindole(8mmol), diethyl(3pyridyl)borane, tetrakis(triphenylphosphine)palladium(0) (400 mg), powdered potassium hydroxyde (32 mmol) andtetrabutylammonium bromide (4 mmol) was refluxed in THF (50 mL) for 48hours. The mixture was then cooled to room temperature, whereafter EtOAc(100 mL) was added. The resulting mixture was then filtered throughfilter aid, and the filtrate was evaporated. The residue was partitionedbetween water (50 mL) and diethyl ether (25 mL). This treatment affordeda crystalline precipitate of the product which was collected byfiltration and washed with water and diethylether, mp. 180-86° C.

EXAMPLE 7 ##STR14##

4-acetamido-7-phenyl-2-methyl-2H-1,3-dihydro-isoindole(2.6 g) was heatedwith stirring at 80° C. for 48 hours in sulphuric acid (66%, 25 mL),whereafter the solution was poured onto ice and then neutralized withaq. NaOH. The precipitated product was collected by filtration, andwashed with water. Mp. 154-550° C.

Similar deacetylations gave:

4-amino-7-(1-naphthyl)-2-methyl-2H-1,3-dihydro-isoindole, mp. 145-48° C.

4-amino-5-nitro -7-phenyl-2-methyl-2H-1,3-dihydro-isoindole, mp 170-72°C.

5-amino-2-methyl-6-nitro-8-phenyl-1,2,3,4-tetrahydro-isoquinoline, mp.128-130° C.

4-amino-7-phenyl-2-ethyl-2H-1,3-dihydro-isoindole hydrochloride, mp.222-225° C.

5-amino-2-methyl-8-phenyl-1,2,3,4-tetrahydro-isoquinoline, m.p. 273-275°C.

EXAMPLE 8 ##STR15##8-amino-2-methyl-5-phenyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride,mp. 210-21° C.,

8-amino-2-methyl-5-(4-fluorophenyl)-1,2,3,4-tetrahydro-isoquinoline, mp.141° C.,

8-amino-2-methyl-5-(4-trifluoromethylphenyl)-1,2,3,4-tetrahydro-isoquinoline,mp. 132-134° C., and

8-amino-2-methyl-5-(4-chlorophenyl)-1,2,3,4-tetrahydro-isoquinolinehydrochloride, mp. 213-215° C.,

were all obtained by hydrogenation using Pd/C as catalyst and ethanol assolvent.

EXAMPLE 9 ##STR16##

A mixture of 4-amino-7-phenyl-2-methyl-2H-1,3-dihydro-isoindole (2.0 g,9 mmol), conc HCl (0.83 ml), 1.5 ml chloral, 10 g of Na₂ SO₄, NH₂ OH(2.0 g) in water (60 mL) was refluxed for two hours, whereafter it wascooled and neutralized with sat. NaHCO₃. The aqueous solution wasdecanted from the oily residue which was dissolved in methylene chloride(100 mL). This solution was dried over Na₂ SO₄, and the solvent wasremoved by evaporation. The residue was dissolved in methane sulphonicacid (3 ml) and heated to 120° C. for 30 min. After cooling to ambienttemperature the solution was diluted with water(20 mL) and neutralizedwith sat. Na₂ CO₃. The impure product was filtered off. Pure7-methyl-5-phenyl-1,6,7,8-tetrahydrobenzo2,1-b:3,4-c!dipyrrole-2,3-dione mp. 187-90° C. was obtained after columnpurification on silica gel using methylene chloride acetone methanol(4:1:1) as eluent.

In a similar manner the following compounds were prepared:

7-ethyl-5-phenyl-1,6,7,8-tetrahydrobenzo2,1-b:3,4-c!dipyrrole-2,3-dione, mp. >250° C.(decomposes).

7-methyl-5-(1-naphthyl)-1,6,7,8-tetrahydrobenzo2,1-b:3,4-c!dipyrrole-2,3-dione-3-oxime in low yield, mp.>300° C.

7-methyl-5-(3-pyridyl)-1,6,7,8-tetrahydrobenzo2,1-b:3,4-c!dipyrrole-2,3-dione-3-oxime.

NMR (¹ H,500 MHz, 6-D DMSO): 2.5 ppm (3H,S), 3.8 ppm (2H,S), 3.9 ppm(2H,S), 6.5-8.7 ppm (5H aromatic, 1S, 4M), 11.0 ppm (1H,S, NH) 13.4 ppm(1H,S,NOH).

8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo3,2-h!isoquinoline-2,3-dione, mp. 280-82° C.

8-methyl-5-(4-chlorophenyl)-6,7,8,9-tetrahydro-1H-pyrrolo3,2-h!isoquinoline-2,3-dione, mp. 225° C. (decomposes).

8-methyl-5-(4-trifluoromethylphenyl)-6,7,8,9-tetrahydro-1H-pyrrolo3,2-h!isoquinoline-2,3-dione, mp. 220-25° C.

8-methyl-5-(4-fluorophenyl)-6,7,8,9-tetrahydro-1H-pyrrolo3,2-h!isoquinoline-2,3-dione, mp. 220-21° C.

7-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo2,3-f!isoquinoline-2,3-dione, m.p.>300° C.

EXAMPLE 10 ##STR17##

4 g of 8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo 3,2-h!isoquinoline-2,3-dione was added in portions to ice-cold chlorosulphonicacid (20 ml). The solution was allowed to stir at room temperature for1/2 hour before it was cooled on ice. Excess chlorosulphonic acid wasthen destroyed carefully with water. After addition of 40 ml of water aheavy precipitate of the sulphonyl chloride was obtained. This solid wasfiltered off and washed with water whereafter, without drying, it wasdissolved in tetrahydrofuran (100 ml). To this solution was dropwiseadded a solution of dimethylamine in tetrahydrofuran(100 ml, 0,5 M). Thefinal mixture was stirred at room temperature for 3 hours and thenevaporated. The oily residue was partitioned between water/Ethylacetate. The organic phase was extracted with 100 ml 0,5 N hydrochloricacid. The aqueous phase was separated and pH adjusted to 9. This causeda precipitate of crude product which could be purified by columncromatography.

EXAMPLE 11 ##STR18##

The product of Example 10 (150 mg), NH₂ OH, CH₃ SO₃ H (100 mg) wasstirred one hour at reflux temperature in ethanol (5 ml) whereafter theprecipitated product was filtered off. Mp. 242-243° C.

EXAMPLE 12 ##STR19##

A mixture of 7-methyl-5-phenyl-1,6,7,8-tetrahydrobenzo2,1-b:3,4-c!dipyrrole-2,3-dione (150 mg), NH₂ OH,HCl (75 mg) and Na₂ CO₃was stirred overnight at room temperature in methanol (5 ml). Water (10ml) was added, and the precipitated product was filtered off. Mp.>300°C.

In a similar manner the following compounds are prepared:

8-methyl-5-(4-nitrophenyl)-6,7,8,9-tetrahydro-1H-pyrrolo3,2-h!isoquinoline-2,3-dione 3-oxime, mp.>300° C.

8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo3,2-h!isoquinoline-2,3-dione 3-o-methyloxime hydrochloride, mp 284-90°C.

7-ethyl-5-phenyl-1,6,7,8-tetrahydrobenzo 2,1-b:3,4-c!dipyrrole-2,3-dione3-oxime hydrochloride, mp.>300° C.

8-methyl-5-(4-chlorophenyl)-6,7,8,9-tetrahydro-1H-pyrrolo3,2-h!isoquinoline-2,3-dione 3-oxime, mp 300-305° C.

8-methyl-5-(4-fluorophenyl)-6,7,8,9-tetrahydro-1H-pyrrolo3,2-h!isoquinoline-2,3-dione 3-oxime, mp 295-300° C.

8-methyl-5-(4-trifluoromethylphenyl)-6,7,8,9-tetrahydro-1H-pyrrolo3,2-h!isoquinoline-2,3-dione 3-oxime, mp 295-300° C.

7-methyl-5-phenyl-6,7,8,9-tetrahyddro-1H-pyrrolo2,3-f!isoquinoline-2,3-dione-3-oxime, m.p.>300° C.

8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo3,2-h!isoquinoline-2,3-dione 3-oxime, mp 280-82° C.

EXAMPLE 13 ##STR20##

Under an atmosphere of nitrogen a mixture of7-ethyl-5-bromo-1,6,7,8tetrahydrobenzo 2,1-b:3,4-c!dipyrrole-2,3-dione3-oxime(0.2 g) and phenyltrimethyltin(0.22 g) was heated to 80° C. indimethylformamide (2 ml). Then a catalytic amount of Bis-triphenylphosphine!-palladium 2! chloride was added. Stirring at 80° C.was continued for 72 hours, whereafter the solvent was evaporated. Theproduct was obtained by chromatography of the residue on silica gelusing EtOAc:MeOH 9:1 as eluent. Mp.>300° C.

EXAMPLE 14 ##STR21##

To a stirred solution of the oxime (300 mg) in AcOH (5ml) acetic acidanhydride (2 ml) was added. The reaction mixture was heated to 80° C.for 30 minutes whereafter it was evaporated in vacuo. The residuecrystallized upon addition of EtOH (10 ml). The crystalline product wascollected by filtration. Mp 190-192° C.

In a similar manner the following compounds are prepared:

7-ethyl-5-phenyl-1,6,7,8-tetrahydrobenzo 2,1-b:3,4-c!dipyrrole-2,3-dione3-O-acetyloxime, mesylate, m.p. 211-213° C.

8-methyl-5-(4-nitrophenyl)-6,7,8,9-tetrahydro-1H-pyrrolo3,2-h!isoquinoline-2,3-dione 3-O-benzoyloxime.

8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo3,2-h!isoquinoline-2,3-dione 3-O-pivaloyloxime, methane sulphonate, m.p.175-176° C.7-ethyl-5-phenyl-1,6,7,8-tetrahydrobenzo2,1-b:3,4-c!dipyrrole-2,3-dione 3-O-phenylacetyloxime.

8-methyl-5-(4-chlorophenyl)-6,7,8,9-tetrahydro-1H-pyrrolo3,2-h!isoquinoline-2,3-dione 3-O-pivaloyloxime. M.p. 175-176° C.

8-methyl-5-(4-fluorophenyl)-6,7,8,9-tetrahydro-1H-pyrrolo3,2-h!isoquinoline-2,3-dione 3-O-acetyloxime.

8-methyl-5-(4-trifluoromethylphenyl)-6,7,8,9-tetrahydro-1H-pyrrolo3,2-h!isoquinoline-2,3-dione 3-O-carbamoyloxime.

EXAMPLE 15 ##STR22##

To a stirred suspension of the oxime (0.5 g) in DMF (5 ml) was added 0.2ml ethylisocyanate. The recation mixture was stirred for three hours atroom temperature whereafter the product was precipitated by addition ofwater (5 ml), filtered off and washed with ethanol. m.p. 140-145° C.decomp (gas evolution)

The following compounds was made in a similar way:

8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo3,2-h!isoquinoline-2,3-dione-3-O-(N-ethyl-carbamoyl)oxime, m.p. 117-118°C.8-methyl-5-(4-(N,N-dimethylsulphamoyl)phenyl)-6,7,8,9-tetrahydro-1H-pyrrolo3,2-h!isoquinoline-2,3-dione-3-O-(N-cyclohexylcarbamoyl)oxime,hydrochloride.

8-methyl-5-(4-(N,N-dimethylsulphamoyl)phenyl-6,7,8,9-tetrahydro-1H-pyrrolo3,2-h!isoquinoline-2,3-dione-3-O-(N-t-butylcarbamoyl)oxime,m.p. 250-260° C., decomp.

7-methyl-5-(4-(N,N-dimethylsulphamoyl)phenyl)-6,7,8,9-tetrahydro-1H-pyrrolo2,3-f!isoquinoline-2,3-dione-3-O-(N-ethylcarbamoyl))oxime

We claim:
 1. A compound having the formula ##STR23## or apharmaceutically acceptable salt thereof whereinR¹ is hydrogen, alkyl orbenzyl; X is NOR², wherein R² is acyl; R⁵ isphenyl, naphthyl, thienyl,pyridyl,all of which may be substituted one or more times withsubstituents selected from the group consisting of halogen, CF₃, NO₂,amino, alkyl, alkoxy, phenyl and SO₂ NR'R" wherein R' and R" eachindependently are hydrogen or alkyl or wherein R' and R" together is(CH₂)_(m) wherein m is 2, 3, 4, 5 or 6; A is a ring of five to sevenatoms fused with the benzo ring at the positions marked a and b, andformed by the following bivalent radicals: a-NR¹² --CH₂ --CH₂ -b a-CH₂--CH₂ --NR¹² -b a-CH₂ --NR¹² --CH₂ -b, a-CH₂ --CH₂ --NR¹² --CH₂ -b,a-CH₂ --NR¹² --CH₂ --CH₂ -b, a-CH₂ --CH₂ --CH₂ --NR¹² -b, a-NR¹² --CH₂--CH₂ --CH₂ -b, a-CH₂ --CH₂ --NR¹² --CH₂ --CH₂ -b, a-CH₂ --CH₂ --CH₂--NR¹² --CH₂ -b, a-CH₂ --NR¹² --CH₂ --CH₂ --CH₂ -b, a-CH₂ --CH₂ --CH₂--CH₂ --NR¹² -b, a-NR¹² --CH₂ --CH₂ --CH₂ --CH₂ -b,wherein R¹² ishydrogen, CH₂ CH₂ OH, or alkyl.
 2. A compound of claim 1 having theformula ##STR24## or a pharmaceutically acceptable salt thereof; whereinX, R¹, R⁵, and R¹² have the meanings set forth above.
 3. A compound ofclaim 1 having the formula ##STR25## or a pharmaceutically acceptablesalt thereof; wherein X, R¹, R⁵, and R¹² have the meanings set forthabove.
 4. A compound of claim 1 having the formula ##STR26## or apharmaceutically acceptable salt thereof; wherein X, R¹, R⁵, and R¹²have the meanings set forth above.
 5. A compound of claim 1 having theformula ##STR27## or a pharmaceutically acceptable salt thereof; whereinX, R¹, R⁵, and R¹² have the meanings set forth above.
 6. A compound ofclaim 1, whichis8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo(3,2-h)isoquinoline-2,3-dione-3-O-acetyloxime,8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo(3,2-h)isoquinoline-2,3-dione-3-O-(N-ethylcarbamoyl)oxime,8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo(3,2-h)isoquinoline-2,3-dione-3-O-pivaloyloxime,7-ethyl-5-phenyl-1,6,7,8-tetrahydrobenzo(2,1-b:3,4-c)-dipyrrole-2,3-dione-3-O-acetyloxime,8-methyl-5-(4-(N,N-dimethylsulphamoyl)phenyl)-6,7,8,9-tetrahydro-1H-pyrrolo3,2-h!isoquinoline-2,3-dione-3-O-(N-ethylcarbamoyl)oxime,8-methyl-5-(4-(N,N-dimethylsulphamoyl)phenyl)-6,7,8,9-tetrahydro-1H-pyrrolo3,2-h!isoquinoline-2,3-dione-3-O-(N-cyclohexylcarbamoyl)oxime, or8-methyl-5-(4-(N,N-dimethylsulphamoyl)phenyl-6,7,8,9-tetrahydro-1H-pyrrolo3,2-h!isoquinoline-2,3-dione-3-O-(N-t-butylcarbamoyl)oxime,or a pharmaceutically acceptable salt thereof.
 7. A pharmaceuticalcomposition comprising a therapeutically-effective amount of a compoundof claim 1 together with at least one pharmaceutically-acceptablecarrier or diluent.
 8. The composition of claim 7, wherein said compoundis present at 0.1 to 100 mg per unit dosage.
 9. The compound of claim 1,wherein said alkyl is a straight or branched chain of one to six carbonsor a cyclic alkyl of three to seven carbons.
 10. The compound of claim9, wherein said alkyl is a group selected from the group consisting ofmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl,hexyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
 11. Thecompound of claim 1, wherein said alkoxy is O-alkyl and -alkyl is astraight or branched chain of one to six carbons or a cyclic alkyl ofthree to seven carbons.
 12. The compound of claim 1, wherein said aminois NH₂, NH-alkyl or N-(alkyl)₂ wherein -alkyl is a straight or branchedchain of one to six carbons or a cyclic alkyl of three to seven carbons.13. The compound of claim 1, wherein said acyl is (C═O)--R° or (C═S)--R°wherein R° is an alkyl, a substituted or unsubstituted phenyl, benzyl,or NR^(III) R^(IV) wherein R^(III) and R^(IV) are each independentlyhydrogen or alkyl or wherein R^(III) and R^(IV) together are (CH₂)_(p)wherein p is 2, 3, 4, 5 or 6; and wherein alkyl is a straight orbranched chain of one to six carbons or a cyclic alkyl of three to sevencarbons.
 14. The compound of claim 1, wherein said compound is in a (+)form.
 15. The compound of claim 1, wherein said compound is in a (-)form.
 16. The compound of claim 1, wherein said compound is racemic. 17.A method of inhibiting GABA release from neurons comprising treatingsaid neurons with an effective amount of the compound of claim
 1. 18. Amethod of treating a disorder or disease of a mammal, which disorder ordisease is responsive to glutamic and/or aspartic acid receptorantagonists, which comprises administering to a patient in need thereofan effective amount of a compound of claim
 1. 19. A method as in claim18 wherein lathyrism, Alzheimer's disease, Huntington's diseases, ALS,schizophrenia, Parkinsonism, epilepsy, excitatory amino acid dependentanxiety, excitatory amino acid dependent pain, drug addiction, orcerebrovascular disorders are treated.
 20. The method of claim 18 or 19,wherein said effective amount is 0.1 to 1000 mg/day.
 21. The method ofclaim 18 or 19, wherein said mammal is a human.
 22. A method ofpreparing a compound of claim 1 comprising the step of reacting acompound having the formula ##STR28## wherein A, a, b, R¹, and R⁵ havethe meanings set forth above, witha) an activated acyl derivative or b)an isocyanateto form a compound of the invention.
 23. The method ofclaim 22, wherein said activated acyl derivative is a carboxylic acid oran anhydride.